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Germ Cell Tumors, Hepatoblastoma & Retinoblastoma. Neyssa Marina, MD Professor of Pediatrics Division of Hematology-Oncology. Pediatric GCT. Rare: 2-3% of childhood malignancies Arise from pluripotent cells & composed of tissues foreign to site of origin

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germ cell tumors hepatoblastoma retinoblastoma

Germ Cell Tumors, Hepatoblastoma & Retinoblastoma

Neyssa Marina, MD

Professor of Pediatrics

Division of Hematology-Oncology

pediatric gct
Pediatric GCT
  • Rare: 2-3% of childhood malignancies
  • Arise from pluripotent cells & composed of tissues foreign to site of origin
  • Occur at gonadal & extragonadal sites
  • Bimodal age distribution
    • Peak < 3 years
      • Extragonadal
      • Testicular tumors
    • Peak: adolescence
      • Gonadal tumors
pediatric gct clinical presentation
Pediatric GCT: Clinical Presentation
  • Depends on primary site:
    • Ovarian: abdominal pain (may mimic acute abdomen), palpable abdominal mass
    • Testicular: Irregular, non-tender masses
    • Extragonadal tumors: depends on tumor location
      • Constipation & urinary retention for sacrococcygeal tumors
      • Respiratory distress for mediastinal tumors
pediatric gct laboratory work up
Pediatric GCT: Laboratory Work-up
  • Alfa fetoprotein (AFP): elevated in yolk sac tumor and embryonal carcinoma; half-life 5-7 days
  • β-Human chorionic gonadotropin (β-HCG): usually synthesized during pregnancy & elevated in choriocarcinoma, embryonal carcinoma and germinomas; half-life 24-36 hours
  • Lactic dehydrogenase (LDH): correlate with tumor burden in patients with dysgerminoma
  • Placental alkaline phosphatase (PLAP): elevated in patients with dysgerminoma
pediatric gct imaging work up
Pediatric GCT: Imaging Work-up
  • CT scan or MRI of primary: to evaluate the extent of loco-regional disease
  • Chest CT: to evaluate presence of metastases
  • Bone scan: to evaluate for distant metastases
gct pediatric versus adult
GCT: Pediatric Versus Adult
  • Histologically
    • Children < 4 years age: endodermal sinus tumor
    • Adolescents: mixed histology tumors
  • Genetically(Schneider, Genes, Chromosomes & Cancer 34:115, 2001)
    • Childhood tumors: diploid & tetraploid
      • Gains of chromosomes (1q, 3 & 20q) & deletions 1p & 6q
    • Adolescent tumors: aneuploid
      • Isochromosome 12p
pediatric gct outcome
Pediatric GCT: Outcome
  • Survival < 20% before use of chemotherapy

Kurman Cancer 38: 2404, 1976.

pediatric gct treatment
Pediatric GCT: Treatment
  • Cyclophosphamide based therapy: improved outcome
    • Advanced stage patients continued to have poor outcome

Cangir, Cancer 42:1234, 1978.

adult gct
Adult GCT
  • Introduction of cisplatin-based therapy curative in adults
    • Einhorn regimen (cisplatin, vinblastine, bleomycin): high-complete remission rate (Einhorn, Ann Int Med 87:293, 1977)
    • Increasing cisplatin dose-intensity: increased toxicity without improving outcome (Nichols, J Clin Oncol 9:1163, 1991)
pediatric gct outcome1
Pediatric GCT: Outcome
  • Although cisplatin-based therapy appeared effective in small number of pediatric patients
    • Significant concerns regarding pulmonary and ototoxicity prevented widespread use of this therapy

Mann, Cancer 63:1657, 1989

Pinkerton, et al. J Clin Oncol, 1986

pediatric gct treatment1
Pediatric GCT: Treatment
  • Based on differences between pediatric and adult tumors, the Pediatric Oncology Group (POG) and the Children’s Cancer Group (CCG) designed two prospective studies
    • Localized gonadal GCT:
      • Stage I testicular: evaluate the event-free survival & overall survival following surgical resection.
      • Stage I/II malignant GCT: evaluate the role of surgery + PEB
    • Advanced GCT:
      • Stage III/IV gonadal & stage I-IV extragonadal: evaluate the role of cisplatin dose-intensity in a randomized trial
stage i testicular efs s
Stage I Testicular: EFS & S
  • 63 patients stage I testicular tumors treated with surgery & observation
    • Age: 1 mo.-5 years
    • Histology: 57 yolk sac carcinoma
    • Failures: 13 patients (median 4 mo. range, 2-18 mo.)
      • Disease recurrence (n=7); median 3 mo. (2-18 mo.)
      • Markers never normalized (n=6); median 4.5 mo. (2-10 mo.)

6-yr S 100%

6-yr EFS 81.8% + 6.6

pediatric gct low stage
Pediatric GCT: Low Stage
  • Stage II testicular
    • 17 patients median age 20 months
  • Ovarian: 57 patients
    • Stage I: 41 patients median age 11.9 years
    • Stage II: 16 patients median age 10.7 years
  • Treatment: surgery + 4-6 cycles PEB

6-yr S: 95.7% + 3.1

6-yr EFS: 94.5% + 3.6

advanced gct study design
Advanced GCT Study Design

Cisplatin 100 mg/m2






Cisplatin 200 mg/m2




advanced pediatric gct patients
Advanced Pediatric GCT: Patients
  • 299 patients diagnosed between February 1990-1996
    • Median age 3.4 years (range 3 days-20 years)
    • 183 female
    • Primary sites
      • 165 extragonadal tumors
      • 134 gonadal tumors
    • Stage distribution:
      • 30 stage I/II
      • 136 stage III
      • 133 stage IV
  • Following surgery patients randomized
    • 150 patients (PEB): 67 gonadal tumors; 83 extragonadal
    • 149 patients (HD-PEB): 67 gonadal; 82 extragonadal
advanced gct efs s by treatment
Advanced GCT: EFS & S by Treatment

6-yr S:91.7% + 3.3

6-yr EFS: 89.6% + 3.6

6-yr S: 86% + 4.1

6-yr EFS: 80.5% + 4.8




extragonadal gct prognostic factors
Extragonadal GCT: Prognostic Factors
  • Extragonadal GCT typically considered high-risk
    • Examine prognostic factors in a large group of patients
  • By multivariate Cox regression for EFS
    • Age > 12 years: only significant prognostic factor (p=0.002)
      • Relative Risk 3.8
    • After adjusting for age, treatment was borderline significant (p=0.064)
  • In multivariate Cox regression for OS, the interaction of age & primary site was highly significant (p<0.0001)
    • Patients > 12 years with thoracic tumors 5.9 times greater risk of death than patients < 12 years or patients with any other primary
gct conclusions
GCT: Conclusions
  • Patients with stage I GCT represent a low-risk group
  • Patients with stage II-III gonadal GCT appear to be an intermediate risk group
  • Patients with advanced extragonadal tumors represent a high-risk group
    • Age > 12 years is the factor most predictive for EFS in these patients
    • There is a significant interaction between age and primary site.
      • This suggests that patients over 12 years with thoracic tumors are biologically different.
pediatric liver tumors
Pediatric Liver Tumors
  • Rare: ~ 1.1% of malignancies
    • 100-150 cases/year in US
    • 0.5-1.5/106 (age < 15 years) in Western countries
    • Affects infants and young children (6 mo – 3yrs; mean age 19 months)
  • Third most common intra-abdominal neoplasm (67% hepatic malignancies < 20 yrs but 91% < 5 years)
  • Hepatocellular carcinoma more frequent than hepatoblastoma in Asia and Africa (hepatitis B infection endemic)
pediatric liver tumors1
Pediatric Liver Tumors
  • Incidence rates for liver tumors: age-dependent

Ries LAG, Smith MA, Gurney JG, Linet M, Tamra T, Young JL, Bunin GR (eds). Cancer Incidence and Survival among Children and Adolescents: United States SEER Program 1975-1995, National Cancer Institute, SEER Program. NIH Pub. No. 99-4649. Bethesda, MD, 1999.

hepatoblastoma risk factors
Hepatoblastoma: Risk Factors
  • Prematurity and low birth weight
    • Disproportionate # of cases with BW < 2500 grams
      • RR 15.64 for BW <1000g, 2.53 for BW 1000-1499g, 1.21 for BW 1500-2499g
  • Association with overgrowth syndromes:
    • Beckwith-Wiedemann (LOH 11p15)
    • Familial adenomatous polyposis (FAP; inactivation of tumor suppressor gene on chromosome 5)
      • Estimated that 1:20 cases of hepatoblastoma have FAP
      • Lifetime risk of hepatoblastoma for children of FAP families: 1/250 compared to 1/100,000 in general population
hepatoblastoma clinical presentation
Hepatoblastoma: Clinical Presentation
  • Asymptomatic abdominal mass
  • Weight loss, anorexia, emesis, and abdominal pain (advanced disease)
  • Distant metastases ~ 20% of cases mostly to lung
    • Intraperitoneal, lymph node, brain, and local tumor thrombus
  • Thrombocytosis is common
    • HB cells secrete IL-1B: induces fibroblasts/endothelial cells to produce IL-6  hepatocyte growth factor secretion and thrombopoeitin secretion
  • 90% of patients have elevated alpha-fetoprotein
  • Rare: hypertension in cases of renin-secreting mixed HB or precocious puberty in HB secreting human chorionic gonadotropin
hepatoblastoma histology
Hepatoblastoma: Histology
  • Derived from undifferentiated embryonal tissue/pluripotent hepatic stem cells
  • Differentiates into hepatocytes, biliary epithelial cells
  • Originally, 2 subtypes recognized
    • Epithelial (mixture of embryonal and fetal)
    • Mixed epithelial and mesenchymal
  • Later classification based on degree of differentiation
    • Embryonal (30%) : tubular or glandular; rosettes of elongated cells
    • Fetal (54%) : highly differentiated; resemble normal hepatocytes with rare mitoses; lack normal lobular architecture
    • Anaplastic/small cell undifferentiated type (6%) : small cells with densely stained nuclei and scant cytoplasm
    • Macrotrabecular (10%) : features similar to hepatocellular carcinoma
hepatoblastoma relevance of histology
Hepatoblastoma: Relevance of Histology
  • Favorable histology defined: “completely resected tumor with a uniform, well-differentiated fetal component exhibiting < 2 mitoses per 10 HPF”
    • Patients treated with surgical resection alone
  • All other histology is considered unfavorable and if stage II-IV, histology is considered irrelevant

Ortega et. al. J Clin Oncology, 2000

hepatoblastoma work up
Hepatoblastoma: Work-Up
  • Diagnostic imaging: important role in diagnosis, staging and treatment
    • Ultrasound: usually first test performed
      • Helps evaluate cystic versus solid masses
    • CT scan or MRI: defines the tumor extent, vascular supply, operability and distant extent of tumor
  • Laboratory work-up:
    • Alfa Fetoprotein: most valuable test
      • Elevated in 80-90% of patients & useful for monitoring
      • Biologic half-life: 5-7 days
hepatoblastoma staging
Hepatoblastoma: Staging
  • Critical to have agreed-upon staging allowing comparison between different studies
  • Early studies of hepatoblastoma showed that surgical resection is the mainstay of therapy and required for cure
    • Staging based on surgical criteria (currently used by German Cooperative Group, CCG, POG)
  • Investigators at SIOP began using preoperative chemotherapy for all patients and thus devised alternative staging system (PRETEXT)
surgically based staging
Surgically-based Staging
  • Stage 1 : complete gross resection with clear margins
  • Stage 2 : Gross total resection with microscopic residual disease at margins
  • Stage 3 : Gross total resection with nodal involvement or tumor spill during resection OR incomplete resection with gross residual intrahepatic disease
  • Stage 4 : Metastatic disease with complete or incomplete resection
pretext staging
  • PRETEXT I: one sector involved
  • PRETEXT II: two sectors involved
  • PRETEXT III: two non-adjoining sectors free or 3 sectors involved
  • PRETEXT IV: all four sectors involved
hepatoblastoma treatment
Hepatoblastoma: Treatment
  • Complete surgical resection: mainstay of therapy
    • Possible at diagnosis: < 50% of patients
    • Surgery: curative > 90% of purely fetal hepatoblastomas
    • 5-year survival with surgery: < 10% other histologies
  • Chemotherapy: used to convert inoperable tumors into resectable tumors
  • Current 5-year survival rate 75%
    • Current objective: improve the prognosis for the 25% of patients who die of disease
new approaches to treatment
New Approaches to Treatment
  • “New Agents”: attempt to increase response rate
  • Chemoembolization: Intra-arterial co-administration of chemotherapeutic and vascular occlusive agents to treat malignant diseases.
  • Liver Transplant: an alternativepatients with unresectable disease following chemotherapy
hepatic chemoembolization
Hepatic Chemoembolization
  • Normal liver parenchyma has dual blood supply:
    • 75%: portal vein
    • 25%: hepatic artery
  • Liver tumors: receive their blood supply almost exclusively from hepatic artery
  • 10% of normal parenchyma: sufficient to maintain metabolic activity
review of world experience
Review of World Experience
  • Authors collected data on 147 cases worldwide : 106 had primary LTX, 41 had rescue LTX
  • OS 72.8%
hepatoblastoma conclusions
Hepatoblastoma: Conclusions
  • The addition of cisplatin-based therapy has improved the outcome for patients with hepatoblastoma
    • Increasing the proportion of patients who can undergo resection
  • Prognosis: sub-optimal for patients with unresectable tumors (following chemotherapy) and for patients with metastases
    • Chemo-embolization and liver transplantation appear to be promising in this subset of patients
    • Identification of new active agents important to attempt to decrease the number of patients with unresectable tumors following chemotherapy
  • Most frequent eye neoplasm in childhood
  • Third most common intraocular malignancy in all ages
    • Malignant melanoma and metastatic carcinoma
  • 2.5-4% of all pediatric cancer
    • 11% of all cancer in children < 1 year of age
    • Two-thirds of cases before 2 years and 95% before 5 years
  • Average age-adjusted incidence rate 2-5/106 children
    • 300 children develop retinoblastoma each year

Two clinical forms

  • Bilateral (~40%): characterized by germline mutations in Rb1 gene
    • Inherited from affected survivor (25%)
    • New germline mutation (75%)
    • 10% unilateral
      • Impossible to tell whether hereditary
  • Unilateral (~ 60% of cases)
  • Arises from fetal retinal cells: lost function of both allelic copies Rb1 gene
    • First event germline or somatic
    • Second event always somatic
    • Mutations in Rb1 detected in 90% cases
      • Another gene or alternate mechanism of inactivation
  • Unique tumor: genetic form predisposes to tumor development in autosomal dominant fashion (85-90% penetrance)
  • Majority of children acquire new mutation (15-25% positive family history)
  • Risk of retinoblastoma in offspring of retinoblastoma survivors
    • Bilateral disease: 45%
    • Unilateral disease: 2.5%
  • Risk of retinoblastoma in siblings:
    • Bilateral disease: 45%
    • Unilateral disease: 30%
retinoblastoma clinical presentation
Retinoblastoma: Clinical Presentation
  • Tumor of the young
  • Age at presentation correlates with laterality
    • Bilateral < 1 year of age
    • Unilateral: 2nd or 3rd year of life
    • Half of cases diagnosed under 1 year: bilateral compared to <10% of cases diagnosed after 1 year
  • Most common presentation leukocoria followed by strabismus
retinoblastoma evaluation
Retinoblastoma: Evaluation
  • Diagnosis made without pathologic confirmation
    • Mass protruding into the vitreous
    • Detailed documentation of number, location & size of tumors as well as retinal detachment, sub-retinal fluid & vitreous, sub-retinal seeds
  • Imaging studies aid diagnosis
    • CT, ultrasound & MRI: important to evaluate extraocular extension
  • Metastases: 10-15% of patients associated with choroidal, scleral invasion or involvement of iris-ciliary body or optic nerve
    • Bone marrow aspirate, CSF & bone scintigraphy to evaluate patients with these findings
retinoblastoma staging
Retinoblastoma: Staging
  • Reese-Ellsworth (R-E) grouping system standard (based on size, location & number of lesions)
    • Does not predict eye salvage
    • New staging systems developed
    • Pathologic staging: features influence treatment & prognosis
retinblastoma staging
Retinblastoma: Staging
  • Extra retinal extension: large intraocular dimension
    • Metastatic risk & mortality: invasion of ocular coats and optic nerve
  • Optic nerve involvement common (25-45%): impact on outcome limited to involvement beyond lamina cribosa
  • Choroidal involvement: up to 40% patients
    • Extensive < 10%: prognostic implication
retinoblastoma treatment
Retinoblastoma: Treatment
  • Treatment: aims at preserving life and useful vision
  • Factors considered:
    • Disease: unilateral vs. bilateral
    • Potential for vision
    • Staging: intra & extra ocular
retinoblastoma treatment1
Retinoblastoma: Treatment
  • Enucleation: large tumors filling the vitreous with no likelihood of restoring vision
    • Ocular implant usually placed
  • Focal treatments: small tumors in patients with bilateral disease combined with chemotherapy
  • Chemotherapy: extraocular disease, intraocular disease with high-risk features and patients with bilateral disease (combined with focal therapies)
  • Radiotherapy: combined with focal treatment provides excellent local control
    • Radiation predisposes to second malignancies: avoid or delay its use
retinoblastoma treatment2
Retinoblastoma: Treatment
  • Outcome: excellent for unilateral disease treated with enucleation (85-90% cure)
    • Successful chemoreduction has led to attempts at salvaging eyes in very young children with unilateral disease
  • Bilateral disease: treated enucleation of eyes with advanced disease and radiation for remaining eyes
    • Up-front chemotherapy to achieve chemoreduction followed by aggressive focal therapy
      • Increase in eye salvage rate & decrease and delay of radiotherapy
      • Best results with carboplatin, vincristine and etoposide
retinoblastoma conclusion
Retinoblastoma: Conclusion
  • The outcome for patients with retinoblastoma is excellent
  • Treatment strategies are aimed at increasing eye salvage rate and decreasing late effects
    • Patients with bilateral disease are at risk for second malignancies
      • The use of radiotherapy increases that risk
  • Genetic counseling is an essential part of treatment for patients with bilateral disease